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Title: Systemic inflammation and its impact on the brain
Author: Drake, Caroline
ISNI:       0000 0004 2720 2470
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Stroke is a leading cause of death in the UK however there is only one current treatment, intravenous thrombolysis via administration of tissue plasminogen activator (tPA). The paucity of available treatments is not simply due to a lack of research as there have been many successful preclinical studies that have failed to translate to success in the clinic. The Stroke Therapy Academic Industry Roundtable (STAIR) have published several articles that outline a number of possible reasons for this lack of translation between pre-clinical and clinical research. One major reason highlighted is the failure to consider clinically relevant co-morbidities in preclinical studies. Therefore the key objectives of this thesis were to; (1) determine whether central nervous system (CNS) changes occur in both animal models and patients with risk factors for stroke, (2) determine how neuroinflammatory changes induced in response to peripheral atherosclerosis are affected by the deletion of IL-1 signalling (3) establish whether a peripheral infection in atherosclerotic mice induces any cerebral ischaemic events and to determine the inflammatory response in both the periphery and the brain. Neuroinflammation was assessed in patients at risk of stroke, the co-morbid JCR-LA rat and the atherosclerotic ApoE-/- mouse. PET imaging revealed microglial activation in the brain of JCR-LA (corpulent) rats and patients at risk of stroke. Microglial activation, vascular activation, leukocyte infiltration and focal lipid deposition were observed in the brains of atherosclerotic ApoE-/- mice. These findings show brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke. Neuroinflammation was assessed in ApoE-/- mice crossed with IL-1 type 1 receptor deficient mice (ApoE-/-/IL-1R1-/-) and both neuroinflammation and systemic atherosclerosiswas assessed in ApoE-/- mice treated with an anti-IL-1β antibody. ApoE-/- mice fed Paigen or Western diet develop vascular inflammation, microglial activation and leukocyte recruitment in the brain, which are absent in ApoE-/-/IL-1R1-/-. Systemic neutralisation of IL-1β with an anti-IL-1β antibody reversed aortic plaque formation and reduced inflammatory cytokin eexpression in peripheral organs. In the brain, vascular inflammation and leukocyte infiltration into the choroid plexus were reversed by IL-1β blockade in animals fed a Paigen diet. Theseresults indicate that IL-1 is a key driver of systemically-mediated cerebrovascularinflammation and that interventions against IL-1β could be therapeutically useful in atherosclerosis, dementia or stroke. ApoE-/- and C57BLJ/6 mice infected with Streptococcus (S.) pneumoniae were assessed for spontaneous stroke events, neuroinflammation and systemic inflammatory responses to infection. Infection with S. pneumoniae in atherosclerotic mice did not induce spontaneous stroke. Raised levels of vascular activation were observed in all mice and an alteration in leukocyte accumulation in infected atherosclerotic ApoE-/- mice. T cell, B cell and granulocyte responses to both diet and infection were found to differ between ApoE-/-mice and control, C57BLJ/6, mice. Levels of the proinflammatory cytokines IL-1, IL-6 andIL-17 were also increased in response to S. pneumoniae infection in plasma, spleen and liver. These data indicate that atherosclerosis and S. pneumoniae infections not only have systemic inflammatory mechanisms but also effects that extend to the brain. Overall these findings demonstrate that risk factors for stroke cause alterations in inflammation in the brain. Therefore modelling of these risk factors is essential in future preclinical stroke research if new treatments for stroke are to be identified.
Supervisor: Allan, Stuart; Rothwell, Nancy; Stratford, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available